Most cytostatic agents which are currently used in anticancer therapy either bind DNA directly (e.g. cisplatin or epirubicine) or target the cytoskeleton (e.g. vinblastine) or the mitotic spindle apparatus (e.g. taxol), thereby directly inhibiting cell cycle progression. For some years it has been well established that phospholipids are also involved in cell growth and intracellular signal transduction. (Cullis, P. R. et al. in Phospholipids and cellular regulation, I. Boca Raton (Ed.), CRC Press, 1-59 (1985); Nishizuka, Y., Science 258: 607-614 (1992)). Phospholipid analogs of high metabolic stability which interfere with these processes and act as proliferation inhibitors have been synthesized. These inhibitors act on a wide variety of cells, including prostate carcinoma, urothelial carcinoma of the bladder, hypernephroid carcinoma and teratocarcinomas (Berdel, W. E. et al., J. Natl. Cancer Inst. 66: 813-817 (1981); Berdel W. E. et al., J. Cancer Res. 43: 5538-5543 (1983); Herrmann, D. B. J., Neumann, H. A., Lipids 22: 955-957 (1987)), various human and murine leukemias, human brain tumors, human lung cancers (Berdel, W. E. et al., Cancer Res. 43: 541-545 (1983); Scholar, E. M. Cancer Lett. 33: 199-204 (1986), and fibrosarcomas (Houlihan, W. J. et al., Lipids 22: 884-890 (1987)). The exact mechanism of action of these phospholipid analogs remains to be elucidated. Primarily, however, the compounds are absorbed into cell membranes where they accumulate and interfere with a wide variety of key enzymes, most of which are membrane associated and are involved in lipid metabolism and/or cell signaling mechanisms (Arthur, G., Bittman, R. Biochim. Biophys. Acta 1390: 85-102 (1998)).
Besides their antiproliferative effects many phospholipid analogs are also potentially toxic, as shown by their lytic properties in cell culture experiments (Wieder, T. et al., J. Biol. Chem. 273: 11025-11031 (1998); Wiese, A. et al., Biol. Chem. 381: 135-144 (2000)), and therefore efforts have been made to synthesise phospholipid analogs with high antiproliferative capacity but low cytotoxic side effects.
The development of phospholipid analogs as antiproliferative agents resulted from the observation that lysophosphatidylcholine (LPC; FIG. 1) played a role in host defense mechanisms (Burdzky, K. et al., Z. Naturforsch. 19b: 1118-1120 (1964). Most commonly used phospholipid analogs are derivatives of lysophosphatidylcholine and lysoplatelet-activating factor (lyso-PAF). Edelfosine, 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3; FIG. 1), is a PAF-derived compound that specifically inhibits the growth of tumor cells, tumor cell invasion, and metastasis and enhances the tumoricidal capacity of macrophages (Houlihan, W. J. et al., Med. Res. Rev. 15: 157-223 (1995)). There are also structurally similar long-chain glycerol-free phosphobase agents, such as hexadecyl-phosphocholine (HePC; FIG. 1), the only compound with therapeutic potential. HePC is currently used for the topical treatment of skin metastases in breast cancer patients (Unger, C. et al., Progr. Exp. Tumor Res. 34: 153-159 (1992); Clive, S., Leonard, R. C. F., Lancet 349: 621-622 (1997)) and visceral leishmaniasis (Jha, T. K. et al., N. Engl. J. Med. 341: 1795-1800 (1999). Due to negative side effects such as high cytotoxicity, efforts have been made to synthesise phospholipid analogs that are less cytotoxic.
Therefore, a novel strategy was followed by introducing sugars or sugar alcohols into the glycerol backbone. The introduction of glucose into the sn-2 position gave rise to glyceroglucophosphocholine (Glc-PC) as well as 1-O-octadecyl-2-O-α-D-gluco-pyranosyl-sn-glycero-3-phosphocholine (Glc-PAF; FIG. 1) (Mickeleit, M. et al., Angew. Chem. Int. Ed. Engl. 34: 2667-2669 (1995); Mickeleit, M. et al., Angew. Chem. Int. Ed. Engl. 37: 351-353 (1998)). Both compounds are water-soluble and display growth inhibitory properties at non-toxic concentrations as discussed further below.
The use of sugar-containing phospholipid analogs has also been described by other groups. Replacement of the sn-3 phosphocholine residue by different monosaccharides results in more effective analogs, compared to non-glycosidated, phosphocholine-containing compounds (Marino-Albernas, J. R. et al., J. Med. Chem. 39: 3241-3247 (1996); Samadder, P., Arthur, G. Cancer Res. 59: 4808-4815 (1998)).
On the other hand it is well known that the metabolism of phosphatidylinositol—having inositol esterified with the phosphate group—liberates intracellular messengers such as inositol-1,4,5-trisphosphate (Lehninger, A. L. et al., Prinzipien der Biochemie, Tschesche, H. (ed.), 2nd edition, Spektrum Akademischer Verlag, 298 (1994)). Therefore, phosphatidylinositol participates in intracellular signal transduction. Inositol containing phospholipids are also known—although without exact structural information and in contexts differing from the one here—from WO 01/82921 A2, WO 02/04959 and JP 2002010796 A.
However, it remained desirable to find phospholipids which were more effective than the ones described before and which—at the same time—had none of the drawbacks as described above.